COMPANY PRESENTATION
INDUSTRIA

Science is our Nature®

DERIVATINATURALIOUR MISSIONAt Indena we believe that an in-depth
knowledge in active ingredients derived
from medicinal plants and the searchfor excellence at all times are crucial
commitments to serving our customers inpharmaceuticals and health-foods.
Research and production technologies
are the main focus of our mission and theway we create a “value difference” for ourpartners.
And we’ve got nearly a century ofexperience to prove it.

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MILESTONES IN THE HISTORY OF INDENA
The origins of the company date back to 1921, when Carlo Boccaccio Inverni began producing extracts from medicinal plants forpharmacists and the emerging Italian pharmaceutical industry. When Biagio Alberto Della Beffa joined as partner and Managing
Director, the firm became a joint-stock company, trading under the name of Dott. Inverni & Della Beffa S.p.A.
During the 1950s, Biagio Alberto’s son Luigi Della Beffa added to the existing business a new pharmaceutical division (Invernidella Beffa S.p.A.) to manufacture and market finished dosage forms from botanical derivatives.
In 1969, a new site for the production of extracts and pure molecules, together with a pivotal research and development centre,
was set up in Settala, near Milan.
In the early 1980s, the botanical derivatives business was reorganised as a new company, Indena S.p.A.
In the 1990s Indena, already present worldwide with a commercial and cultivation network, opened new production plants,
notably in France and India, and additional commercial branches.
Throughout its long history, Indena has specialised in the identification, development and production of plant derived purified
extracts and pharmaceutical active principles including flavonoids, glycosides, aminoacids, alkaloids and their semi-synthetic
derivatives.

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FACTS & FIGURES
800 employees
5 international branches
4 production sites worldwide
sales in more than 80 countries
more than 100 primary patents|5THE INDENA MARKET
ORGANISATION

Pharmaceuticaldirect presence

32%

BUSINESS SECTORS

Health-foodsales organisation

42%

production

20%

Organic synthesis

High containment

Sustainability

Nagoya convention

INDENA’S PILLARS
Nearly a century of history based onfour “pillars”.
Processdevelopment

Clinical testing

Safety andtoxicity studies

Plus continuous
attention tosustainability
and environmental
impact.

OECD

Stability

Formulation
development

ANSM
Health Ingredientsdevelopment

FDA

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A RESEARCH BASED COMPANY
At Indena, we have always been inspired by a rigorous scientific approach in our research.
In PROCESS RESEARCH, original advanced industrial production processes are designed andengineered for work on existing or new molecules, as well as for the development of new APIsand HPAPIs
In PRODUCT RESEARCH we focus on active ingredients for the health and nutrition market,
supporting them with safety and efficacy data and applying innovative delivery technologies asneeded.

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BOTANICAL SOURCES
In addition to traditional gathering of wild plants, Indena hasestablished a worldwide network of plantations to provide highquality vegetal raw material.
Internationally recognised botanical experts monitor more than
3,000 hectares of Good Agricultural and Collection Practices(GACP) compliant plantations, which today account for more than
60% of the vegetal raw material we use.
We pursue the highest botanical standards with maximum respect
for the environment and biodiversity.
To achieve well-identified and consistently high-quality vegetal raw
material, we use micropropagation and traditional plant breeding,but never GMO.

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INDENA PRODUCTION
Advanced, highly flexible and environment-friendly state-of-the-art
technology is used throughout the Indena manufacturing cycle.
Indena’s facilities incorporate separate authorised areas for handlingpharma and food grade natural derivatives, where the Quality
System ensures compliance with cGMP and Hazard Analysis andCritical Control Points (HACCP) guidelines.
With more than 100 DMFs, Indena’s pharmaceutical products
meet US-FDA and EU requirements, and two production sites areaccredited by Japanese authorities.
Health-food pre-mixed preparation.
Fermentation production capabilities.
Spray drying capabilities from organic solvents on different scales,developed in decades of operations.

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MAIN PRODUCTION
EQUIPMENTS AT OUR SITES
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Grinding apparatus (hammer- and knife-grinders) | plant material grinding
Percolators (static and dynamic) | plant material extraction
Reactors | reaction, crystallisation, concentration
Concentrators (thin-film concentrators) | solvent evaporation
Liquid-liquid extractors | selective extraction, purification process
Columns for chromatography | concentration, purification, isolation
Centrifuges, filter-press | solid-liquid separation
Driers (tray driers, driers with stirring, microwave) | drying
Spray dryers | Spray drying
Mills and sieves | milling and sieving of powders
Mixers | blending of powders, standardisation|17

PROCESS DESIGN FOR
HIGH-CONTAINMENT SYNTHESISPROCESS DEVELOPMENT & SCALING-UP CAPABILITIES:• Process design for High Potency Compounds synthesis• Route optimisation (statistical Design Of Experiment) and scale-up• Preparation of small scale material, from grams to kilograms• cGMP manufacturing of APIs for clinical trials
ANALYTICAL & PRECLINICAL SUPPORT:
Related substances and secondary metabolites identification• Support to process development• IPC and release analysis for GMP production• Solid state characterization and polymorphism screening for IP protection• Investigational and regulatory stability studies• Collaboration with the most important international analytical organizations (EP and USP, AOAC) topromote analytical methods innovation•

PRODUCTION SCALE CAPABILITIES:First purification of cytotoxic APIs
• Final purification and drying of cytotoxic APIs
• Semi-and-total-synthesis of HPAPIs• Availability of industrial suites (equipped with 20 linear meter glove boxes)• Availability of 2 kilolabs (LK1 and LK2) for clinical and smaller scale commercial supplies of HPAPIs
with OEL 20 ng/m3• Lab, pilot and industrial scale multipurpose fermentation plants• Intermediate and large scale spray dryers, both working with class 2 organic solvents, also in thepresence of excipients/co-polymers (for drug product intermediates)•|19

INDENA QUALITY
1_ Quality of the raw material:• identification of the plant through specific protocol and analyses, such as botanical checks, chromatographic profiles, orDNA analysis;• purification of the botanical extract: if the plant contains toxic, allergenic or unwanted substances, it is important toremove these components and obtain an extract deemed purified;• standardization combines different lots to ensure that the botanical extract always has the same composition of constituents.
2_ Control of the supply chain:• suppliers are accredited on the basis of rigorous criteria of quality, sustainability and traceability;• GAPC guidelines for good agricultural and collection practices are implemented in the supply chain;• the need for high quality raw materials is reconciled with the principles of biodiversity and sustainability indicated byinternational conventions and standards such as the Convention on Biological Diversity (CBD);• the entire supply chain is under continuous control from cultivation to the delivery of the raw material to the production
sites.
3_ Quality of the manufacturing processes:• technologically advanced and safe production plants for both raw materials and operators;• process compliant with production standards and regulations such as Good Manufacturing Practices (GMP) and the Hazard
Analysis Critical Control Points manual (HACCP);• use of high-quality, precisely defined excipients to optimize the effectiveness of the active ingredient;• meticulous inspection of the finished product.

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SUSTAINABILITY & THE ENVIRONMENT
Nature has always been for Indena both a source of inspiration and an essential resource. We have always been consciousof how important it is to preserve and regenerate the natural balance of every living source and for this we strictly
follow laws, guidelines, procedures and programs with the aim of guaranteeing the safety of employees, safeguarding
environment and biodiversity. These aims lie at the heart of the projects undertaken within the Sustainable Sourcing
Program and dedicated to the communities involved in the collection of the many species that Indena markets. On
the other side, the ever increasing effort to reduce the environmental impact of production sites has led to significant
results in its main facilities, all certified ISO 14001 and OHSAS 18001.

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ACTIVE PHARMACEUTICALINGREDIENTSPHARMACEUTICAL

Isolated or semisynthetic pure products and extracts are produced in compliance withcGMP and supported by CTD-DMFs.
Among our main products:

PACLITAXEL

Taxus media Rehder - Root, leaf and twig - ≥97.0% ≤102.0% by HPLC - Anticancer

10-DAB III

Taxus baccata L. - Twig and leaf - ≥96.0% by HPLC - Chemical intermediate

THIOCOLCHICOSIDE

Gloriosa superba L. - Seed - ≥98.0% ≤102.0% by potentiometry - Muscle relaxant

COLCHICINEGloriosa superba L. - Seed - ≥97.0% ≤102.0% by potentiometry - Antigout

DOCETAXEL

Taxus baccata L. - Twig and leaf - ≥97.0% ≤102.0% by HPLC - Anticancer

MYRTOCYAN®

Vaccinium myrtillus L. - Fresh frozen fruit - ≥32.4% ≤39.6% of anthocyanins, 1.0% anthocyanidins by HPLC
- Capillarotropic

ESCIN

Aesculus hippocastanum L. - Seed - ≥97.0% ≤103.0% by potentiometry - Antioedema

GINKGO BILOBA

Ginkgo biloba L. - Leaf - ≥22.0% ≤27.0% of flavonoids, ≥2.6% ≤3.2% of bilobalide, ≥2.8% ≤3.4% of ginkgolides
A,B,C, ≤5 ppm of ginkgolic acids by HPLC - Blood circulation improver|25

HEALTH - FOOD INGREDIENTS
Indena leverages its solid pharmaceutical background for the health-food field, developing
biologically active ingredients for supplements, functional, medical and baby food products
for more than 40 years. These include:

BEANBLOCK®

HEALTH - FOOD

Phaseolus vulgaris L. - Common bean - ≥6.0% as alpha amylase inhibitor by HPLC - 1,100 U/mg of alpha amylase inhibiting
activity, ≥10,000 ≤30,000 HAU/g of hemagglutinating activity by spectroph./enzym. - Appetite regulator, Healthy blood
sugar metabolism

GREENSELECT®

Camellia sinensis (L.) O. Kuntze - Young leaf - ≥60.0% of total polyphenols, ≥40.0% of (-)-epigallocatechin-3-O-gallate,

LEUCOSELECT®

Vitis vinifera L. - Seed - ≥95.0% ≤105.0% of proanthocyanidins by GPC - ≥13.0% ≤19.0% of catechin and epicatechin by
HPLC - Antioxidant activity, Circulatory health

MIRTOSELECT®

Vaccinium myrtillus L. - Fresh frozen fruit - ≥36.0% of anthocyanins by HPLC - ≥25.0% of anthocyanins as anthocyanidins
by spectrophotometry - Eye health, Circulatory health, Antioxidant activity

MITIDOL®

Zingiber officinale Roscoe - rhizome + Acmella oleracea L. – flowers - ≥2.4 ≤3.9% total gingerols and shogaols - ≥0.30≤0.60% spilanthol by HPLC - Natural ache relief

OPEXTAN®

Olea europaea L. - Fruit - ≥10.0% of total polyphenols by spectrophotometry - ≥2.0% ≤3.5% of verbascoside, ≥4.5% ofhydroxytyrosol and its derivatives by HPLC - Antioxidant activity, Healthy skin, Healthy cardiovascular function

PRODIGEST®

Cynara cardunculus L. + Zingiber officinale Roscoe - Artichoke extract - ≥28.0 ≤34.0% by HPLC Ginger extract - ≥6.0%≤7.0% by HPLC - Digestive healthIndena standardised extracts have full chemical characterisation backed by QUALITY,SAFETY AND EFFICACY TESTS.

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HEALTH - FOOD INGREDIENTSHEALTH - FOOD

Indena has developed a proprietary technology to optimise the bioavailability of selected
phytochemicals. Products include:

CASPEROME®

Boswellia serrata Roxb. ex Colebr. - Resin - ≥25.0% of boswellic acids by HPLC - For healthy inflammatory response

GINKGOSELECT®

Ginkgo biloba L. - Leaf - ≥7.0% of ginkgoflavonglucosides, ≥2.0% of ginkgoterpenes, ≥0.8% of bilobalide, ≥0.8% of
ginkgolides, ≤5 ppm of total ginkgolic acids by HPLC - Cognition and circulation improver, Antioxidant activity, Vasokinetic

GREENSELECT®

Camellia sinensis (L.) O. Kuntze - Young leaf - ≥19.0% ≤25.0% of polyphenols expressed as (-)-epigallocatechin-3-O-gallate,≥13.0% of (-)-epigallocatechin-3-O-gallate, ≤0.1% of caffeine by HPLC - Antioxidant activity, Weight loss agent

MERIVA®

Curcuma longa L. - Rhizome - ≥18.0% ≤22.0% of curcuminoids by HPLC - Joint health, For healthy inflammatory response

QUERCEFIT TM

Sophora japonica L. – Flowers - ≥34.0% ≤42.0% of quercetin by HPLC - Sports nutrition, allergy seasons’ discomforts
control, antioxidant activity

SILIPHOS®

Silybum marianum (L.) Gaertn. - Fruit - ≥29.7% ≤36.3% of silybin by HPLC - Healthy liverUBIQSOME®

CoQ10 Phytosome® - 18-22% of coenzyme Q10 by HPLC - Cellular energy

VAZGUARDTM

Citrus bergamia Risso & Poit. - Fruit juice - ≥11.0% ≤19.0% of total flavanols by HPLC - Cardiovascular health|29

FLAVOURS
Botanical extracts with organoleptic properties

AMMONIUM GLYCYRRHIZATE

Glycyrrhiza glabra L. - Root | ≥98.0% ≤102.0% of monoammonium glycyrrhizate

ANISE

FLAVOURS

Illicium verum Hooker fil. - Fruit | ≥0.5% of anethole by GC

CHAMOMILE

Matricaria recutita L. - Flowering head | ≥1.2% of total apigenin by HPLCGINSENG 1/2/10%

Panax ginseng C.A. Meyer - Root | 1.0, 2.0, 10% of total ginsenosides and malonylginsenosides calculated on the dried substance by colorimetry

GRAPE SEED

Vitis vinifera L. - Seed | ≥95.0% of proanthocyanidins by spectrophotometry, ≥5.0%≤15.0% of catechin and epicatechin by HPLC

GUARANA

Paullinia cupana H.B. et K. - Seed | 12% of total alkaloids by HPLCLEMON BALM

Melissa officinalis L. - Flowering head | ≥10% of hydroxycinnamic derivates calculated
as rosmarinic acid

OPLODEX™

Quercus spp. Wood - Camellia sinensis (L.) O. Kuntze Leaf - Vitis vinifera L. Seed |Balanced and synergistic combination of polyphenolic botanical extracts

QUASSELECT®

Quassia amara L. Wood | ≥53.0% ≤57.0% as sum of quassin and neoquassin by HPLC

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CDMO

CONTRACT DEVELOPMENT AND MANUFACTURING ORGANIZATIONCUSTOM SERVICES
With a century long experience and continuous technological expansion, Indena has focused on Contract
Development and Manufacturing services for its partners, supporting product development from clinical
trials to large scale commercial manufacturing.
Indena’s R&D center is in Italy, while the production units are in Italy (Settala and Palestro), France and Indiaand incorporate separate authorised areas for handling pharma and food grade natural derivatives, and the
Quality System ensures compliance with cGMP and Hazard Analysis and Crytical Control Points (HACCP)
guidelines.

CYTOTOXICS AND HPAPIs
Indena HPAPIs contract manufacturing services include a full range of dedicated development andmanufacturing solutions such as fermentation, extraction, isolation, purification, synthetic modifications andtotal synthesis for active pharmaceutical ingredients on a wide range of scales.
This facility incorporates appropriate room pressurization, airlocks, ventilation and isolators to properly
handle highly potent solids and liquids down to 20 ng/m3 OEL (SafeBridge® Class 4).
Settala site is regularly inspected by the main Regulatory Authorities.

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DISSEMINATING KNOWLEDGE
ON MEDICINAL PLANTS
Indena acts to foster interest in medicinal plants and natural products:•

By founding Fitoterapia, a Journal published since 1924 and today recognised as a premiersource for research on medicinal plants (2012 Impact Factor: 2.231, currently distributed by
Elsevier)•

By publishing monographs and books on medicinal plants•

By sponsoring Masters and specialist schools in phytotherapy•

By offering scholarship grants to young researchers|35

THE INDENA ORGANISATIONHEADQUARTERS

INTERNATIONAL BRANCHES

Indena S.p.A. | Milan | Italy

Indena Biotechnology (Shanghai) Co., Ltd. | China
Indena Brasil Ltda | São Paulo | Brazil
Indena Japan Co., Ltd. | Tokyo | Japan
Indena S.A.S. | Paris | France
Indena USA Inc. | Seattle | WA | USA

RESEARCH CENTRE
Indena S.p.A. | Settala (MI) | Italy|37

THE INDENAPRODUCTION SITES
Indena S.p.A. | Settala (MI) | Italy
Bernett S.r.l. | Palestro (PV) | Italy
Indena S.A.S. | Tours | France
Indena India Pvt. Ltd. | Bangalore | India

Indena S.p.A. | Settala (MI) | Italy

Bernett S.r.l. | Palestro (PV) | Italy

Indena S.A.S. | Tours | France

Indena India Pvt. Ltd. | Bangalore | India

INNOVATIONTRADITIONEXCELLENCEQUALITY

INDENA.COM